RESUMEN
Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model
La disfunción del tejido adiposo perivascular del lecho mesentérico posee una participación en la fisiopatología de la hipertensión arterial relacionada con el síndrome metabólico. Por lo tanto, podría considerarse como un nuevo blanco terapéutico en las enfermedades cardiovasculares y metabólicas. Además de su efecto antihipertensivo, existe un interés creciente en las acciones pleiotrópicas de losartán, antagonista del receptor de angiotensina II. El objetivo del estudio fue analizar las acciones de losartán sobre el índice de adiposidad y la liberación de prostanoides del lecho vascular mesentérico y su relación con la presión arterial, así como en el índice HOMA-IR (modelo de evaluación homeostático de la resistencia a la insulina) en ratas con dieta alta en grasas. Observamos que la dieta alta en grasas incrementó la adiposidad del lecho vascular mesentérico y la liberación de prostanoides vasoconstrictores como tromboxano (TX) B2 y prostaglandina (PG) F2α, así como la PGE2, un prostanoide inflamatorio en el contexto de resistencia a la insulina e hipertensión. También encontramos una correlación positiva entre el índice de adiposidad y la presión arterial sistólica y ambos parámetros se correlacionan positivamente con el índice HOMA IR. Adicionalmente observamos que la liberación de estos prostanoides se correlaciona con la presión arterial sistólica, así como con el índice de adiposidad del lecho vascular mesentérico. El tratamiento con losartán previno todas estas alteraciones y normalizó la relación PGI2/TXA2 en ratas alimentadas con una dieta alta en grasa. Concluimos entonces que losartán puede ejercer acciones beneficiosas sobre las alteraciones del tejido adiposo perivascular y la disfunción endotelial a través de la restauración del equilibrio normal de sustancias vasoactivas en este modelo experimental
Asunto(s)
Animales , Ratas , Hipertensión/tratamiento farmacológico , Losartán/farmacocinética , Oclusión Vascular Mesentérica/prevención & control , Obesidad/fisiopatología , Síndrome Metabólico/fisiopatología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Antihipertensivos/farmacocinética , Resistencia Vascular/efectos de los fármacos , Hipertensión/fisiopatología , Ácidos ProstanoicosRESUMEN
Currently, anticoagulants would be used to prevent thrombosis. Thrombin is an effector enzyme for haemostasis and thrombosis. We designed a direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modelling and demonstrated that the C-terminus of DTIP interacts with exosite I, and N-terminus with the activity site of thrombin, respectively. DTIP interfered with thrombin-mediated coagulation in human, rat and mouse plasma (n=10 per group) and blocked clotting in human whole blood in vitro. When administered subcutaneously, DTIP showed potent and dose-dependent extension of aPTT, PT, TT and CT in rats (n=10 per group). The antithrombotic dose of DTIP induced significantly less bleeding than bivalirudin determined by transecting distal tail assay in rats. Furthermore, DTIP reached peak blood concentration in 0.5-1 hour and did not cause increased bleeding after five days of dosing compared to dabigatran etexilate. The antithrombotic effect of DTIP was evaluated in mice using lethal pulmonary thromboembolism model and FeCl3-induced mesenteric arteriole thrombus model. DTIP (1.0 mg/kg, sc) prevented deep venous thrombosis and increased the survival rate associated with pulmonary thromboembolism from 30 % to 80 %. Intravital microscopy showed that DTIP (1.0 mg/kg, sc) decelerated mesenteric arteriole thrombosis caused by FeCl3 injury. These data establish that DTIP is a novel antithrombotic agent that could be used to prevent thrombosis without conferring an increased bleeding risk.
Asunto(s)
Antitrombinas/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Hirudinas/administración & dosificación , Oclusión Vascular Mesentérica/prevención & control , Embolia Pulmonar/prevención & control , Trombina/antagonistas & inhibidores , Trombosis de la Vena/prevención & control , Animales , Antitrombinas/toxicidad , Pruebas de Coagulación Sanguínea , Cloruros , Colágeno , Dabigatrán/administración & dosificación , Dabigatrán/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epinefrina , Compuestos Férricos , Hemorragia/inducido químicamente , Hirudinas/toxicidad , Humanos , Inyecciones Subcutáneas , Masculino , Oclusión Vascular Mesentérica/sangre , Oclusión Vascular Mesentérica/inducido químicamente , Ratones Endogámicos C57BL , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/toxicidad , Embolia Pulmonar/sangre , Embolia Pulmonar/inducido químicamente , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/toxicidad , Factores de Riesgo , Trombina/metabolismo , Factores de Tiempo , Trombosis de la Vena/sangre , Trombosis de la Vena/inducido químicamenteRESUMEN
PURPOSE: Vogt´s antioxidant solution (red blood cells, Ringer's solution, sodium bicarbonate, mannitol, allopurinol and 50% glucose) or its modification including hydroxyethyl starch (HES) were tested for the prevention of splanchnic artery occlusion shock. METHODS: Seventy rats were distributed in treatment (3), control (1), and sham (3) groups. Ischemia and reperfusion were induced by celiac, superior mesenteric and inferior mesenteric arteries occlusion for 40 min, followed by 60 min reperfusion or sham procedures. Controls received saline, both treatment and sham groups received the Vogt's solution, modified Vogt's solution (replacing Ringer's solution by HES), or HES. Mean arterial blood pressure (MABP), ileal malondialdehyde (MDA) and plasmatic MDA were determined, and a histologic grading system was used. RESULTS: At reperfusion, MABP dropped in all I/R groups. Only HES treatment was able to restore final MABP to the levels of sham groups. Plasmatic MDA did not show differences between groups. Ileum MDA was significantly higher in the control and treatment groups as compared to the sham group. Histology ranking was higher in the only in control group. CONCLUSIONS: Hydroxyethyl starch was able to prevent hemodynamic shock but not intestinal lesions. Both treatments with Vogt's solutions did not show any improvement.
Asunto(s)
Derivados de Hidroxietil Almidón/farmacología , Arterias Mesentéricas/efectos de los fármacos , Oclusión Vascular Mesentérica/prevención & control , Sustitutos del Plasma/farmacología , Daño por Reperfusión/prevención & control , Animales , Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Derivados de Hidroxietil Almidón/uso terapéutico , Íleon/irrigación sanguínea , Íleon/patología , Isquemia/prevención & control , Soluciones Isotónicas/farmacología , Soluciones Isotónicas/uso terapéutico , Masculino , Malondialdehído/análisis , Arterias Mesentéricas/patología , Oclusión Vascular Mesentérica/patología , Sustitutos del Plasma/uso terapéutico , Ratas Wistar , Reproducibilidad de los Resultados , Circulación Esplácnica/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Vogt´s antioxidant solution (red blood cells, Ringer's solution, sodium bicarbonate, mannitol, allopurinol and 50% glucose) or its modification including hydroxyethyl starch (HES) were tested for the prevention of splanchnic artery occlusion shock. METHODS: Seventy rats were distributed in treatment (3), control (1), and sham (3) groups. Ischemia and reperfusion were induced by celiac, superior mesenteric and inferior mesenteric arteries occlusion for 40 min, followed by 60 min reperfusion or sham procedures. Controls received saline, both treatment and sham groups received the Vogt's solution, modified Vogt's solution (replacing Ringer's solution by HES), or HES. Mean arterial blood pressure (MABP), ileal malondialdehyde (MDA) and plasmatic MDA were determined, and a histologic grading system was used. RESULTS: At reperfusion, MABP dropped in all I/R groups. Only HES treatment was able to restore final MABP to the levels of sham groups. Plasmatic MDA did not show differences between groups. Ileum MDA was significantly higher in the control and treatment groups as compared to the sham group. Histology ranking was higher in the only in control group. CONCLUSIONS: Hydroxyethyl starch was able to prevent hemodynamic shock but not intestinal lesions. Both treatments with Vogt's solutions did not show any improvement. .
Asunto(s)
Animales , Masculino , Derivados de Hidroxietil Almidón/farmacología , Arterias Mesentéricas/efectos de los fármacos , Oclusión Vascular Mesentérica/prevención & control , Sustitutos del Plasma/farmacología , Daño por Reperfusión/prevención & control , Modelos Animales de Enfermedad , Hemodinámica/efectos de los fármacos , Derivados de Hidroxietil Almidón/uso terapéutico , Íleon/irrigación sanguínea , Íleon/patología , Isquemia/prevención & control , Soluciones Isotónicas/farmacología , Soluciones Isotónicas/uso terapéutico , Malondialdehído/análisis , Arterias Mesentéricas/patología , Oclusión Vascular Mesentérica/patología , Sustitutos del Plasma/uso terapéutico , Ratas Wistar , Reproducibilidad de los Resultados , Circulación Esplácnica/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Factor VII (FVII) activating protease (FSAP) is a circulating protease with a putative function in blood coagulation and fibrinolysis. Genetic epidemiological studies have implied a role for FSAP in carotid stenosis, stroke and thrombosis. To date, no in vivo evidence is available to support these claims. We have, for the first time, used FSAP-/- mice to define its role in thrombosis and haemostasis in vivo and to characterise the molecular mechanisms involved. FeCl3-induced arterial thrombosis in carotid and mesenteric artery revealed that the occlusion time was significantly increased in FSAP-/- mice (p< 0.01) and that some FSAP-/- mice did not occlude at all. FSAP-/- mice were protected from lethal pulmonary thromboembolism induced by collagen/ epinephrine infusion (p< 0.01). Although no spontaneous bleeding was evident, in the tail bleeding assay a re-bleeding pattern was observed in FSAP-/- mice. To explain these observations at a mechanistic level we then determined how haemostasis factors and putative FSAP substrates were altered in FSAP-/- mice. Tissue factor pathway inhibitor (TFPI) levels were higher in FSAP-/- mice compared to WT mice whereas FVIIa levels were unchanged. Other coagulation factors as well as markers of platelet activation and function revealed no significant differences between WT and FSAP-/- mice. This phenotype of FSAP-/- mice could be reversed by application of exogenous FSAP. In conclusion, a lack of endogenous FSAP impaired the formation of stable, occlusive thrombi in mice. The underlying in vivo effect of FSAP is more likely to be related to the modulation of TFPI rather than FVIIa.
Asunto(s)
Enfermedades de las Arterias Carótidas/prevención & control , Hemostasis , Oclusión Vascular Mesentérica/prevención & control , Serina Endopeptidasas/deficiencia , Trombosis/prevención & control , Tromboembolia Venosa/enzimología , Animales , Pruebas de Coagulación Sanguínea , Arterias Carótidas/enzimología , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/inducido químicamente , Enfermedades de las Arterias Carótidas/enzimología , Enfermedades de las Arterias Carótidas/genética , Cloruros , Colágeno , Modelos Animales de Enfermedad , Compuestos Férricos , Predisposición Genética a la Enfermedad , Hemostasis/genética , Venas Yugulares/enzimología , Lipoproteínas/sangre , Arterias Mesentéricas/enzimología , Oclusión Vascular Mesentérica/sangre , Oclusión Vascular Mesentérica/inducido químicamente , Oclusión Vascular Mesentérica/enzimología , Oclusión Vascular Mesentérica/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Norepinefrina , Fenotipo , Serina Endopeptidasas/administración & dosificación , Serina Endopeptidasas/genética , Trombosis/sangre , Trombosis/inducido químicamente , Trombosis/enzimología , Trombosis/genética , Tromboembolia Venosa/sangre , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/genéticaRESUMEN
BACKGROUND: Intestinal ischemia is associated with a very high mortality rate. We combined the principles of Virchow's triad to produce preoperative and postoperative models for the development of intestinal ischemia. METHODS: A single institutional study was undertaken involving 18,325 consecutive patients from April 1997 to March 2012. Univariate and multivariate analysis was performed. RESULTS: Mortality was 87% in 91 patients who developed bowel ischemia. Multivariate logistic regression demonstrated that age, peripheral vascular disease, intraaortic balloon pump support, female sex, and preexisting renal failure were significant determinates of intestinal ischemia preoperatively. Logistic regression demonstrated that age, peripheral vascular disease, creatine kinase-MB level, reoperation for bleeding, and blood product usage were significant determinates of intestinal ischemia postoperatively. CONCLUSIONS: Potentially remedial causes of intestinal ischemia include blood product usage, reoperation for bleeding, and creatine kinase-MB release. Age, female sex, peripheral vascular disease, intraaortic balloon pump usage, and preexisting renal failure are fixed risk factors. Despite the continuing trend of reduced blood product usage in the field of cardiac surgery, the increase in patients' risk factors will mean that incidences of intestinal ischemia may increase in the future.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos/efectos adversos , Isquemia Mesentérica/etiología , Oclusión Vascular Mesentérica/etiología , Trombosis/etiología , Factores de Edad , Anciano , Procedimientos Quirúrgicos Cardíacos/mortalidad , Comorbilidad , Inglaterra , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Isquemia Mesentérica/diagnóstico , Isquemia Mesentérica/mortalidad , Isquemia Mesentérica/prevención & control , Oclusión Vascular Mesentérica/diagnóstico , Oclusión Vascular Mesentérica/mortalidad , Oclusión Vascular Mesentérica/prevención & control , Persona de Mediana Edad , Análisis Multivariante , Redes Neurales de la Computación , Oportunidad Relativa , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/cirugía , Reoperación , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Trombosis/diagnóstico , Trombosis/mortalidad , Trombosis/prevención & control , Factores de Tiempo , Reacción a la Transfusión , Resultado del TratamientoRESUMEN
The link between cancer and venous thromboembolism is well known, with an annual incidence rate of venous thromboembolism between 0.5% and 20% depending on the primary site and background risk factors. Current guidelines suggest treatment with low-molecular-weight heparin over oral vitamin K antagonists. However, data regarding the management of recurrent venous thromboembolism when the patient is under treatment with anticoagulants are sparse. In this article we present a patient with multiple thromboembolic events in unusual sites despite anticoagulant treatment and we discuss the management options.
Asunto(s)
Adenocarcinoma/secundario , Carcinoma de Pulmón de Células no Pequeñas/secundario , Fibrinolíticos/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Neoplasias Pulmonares , Trombosis/prevención & control , Tromboembolia Venosa/prevención & control , Resultado Fatal , Humanos , Venas Yugulares , Neoplasias Pulmonares/complicaciones , Masculino , Arteria Mesentérica Superior , Oclusión Vascular Mesentérica/etiología , Oclusión Vascular Mesentérica/prevención & control , Persona de Mediana Edad , Prevención Secundaria , Vena Subclavia , Trombosis/etiología , Tinzaparina , Insuficiencia del Tratamiento , Tromboembolia Venosa/etiología , Trombosis de la Vena/etiología , Trombosis de la Vena/prevención & controlRESUMEN
Stent fracture after fenestrated endovascular aneurysm repair is a recognized complication. In this report, we record the occurrence of superior mesenteric artery stent fractures in our series and describe the management of embolized stent fragments during secondary intervention.
Asunto(s)
Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Procedimientos Endovasculares/instrumentación , Arteria Mesentérica Superior/cirugía , Falla de Prótesis , Stents , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aortografía , Implantación de Prótesis Vascular/efectos adversos , Remoción de Dispositivos , Embolia/etiología , Embolia/terapia , Procedimientos Endovasculares/efectos adversos , Humanos , Masculino , Arteria Mesentérica Superior/diagnóstico por imagen , Oclusión Vascular Mesentérica/etiología , Oclusión Vascular Mesentérica/prevención & control , Diseño de PrótesisRESUMEN
Ghrelin is an important hormone involved in the control of the human appetite center. Recently, protective properties of this hormone have been recognized in various models of impairment of the gastric mucosa, including stress, ischemia and reperfusion (I/R). Ghrelin is predominantly secreted by the gastric mucosa of stomach, but there are other sources of ghrelin, for example in the hypothalamus and various parts of the central nervous system (CNS) that should be taken into consideration. This hormone exerts biological effects via the activation of growth hormone secretagogue receptor (GHSR), the presence of which was confirmed in different parts of the gastrointestinal (GI) tract and midbrain structures. Although substantial evidence of the divergent biological effects of ghrelin and the mechanism of its action has been emphasized, the precise mechanisms of ghrelin which affords GI protection is still unclear. Particularly, there is a sparse amount of evidence concerning its action on the GI system. The major aim of the present study was to evaluate the importance of peripherally and centrally administered ghrelin at different times of the ischemia and reperfusion (I/R period in the modulation of resistance of the intestinal mucosa to the injury induced by ischemia and subsequent reperfusion. Secondly, we wanted to evaluate the possible mechanism of the action of ghrelin with a particular focus on its influence on the intestinal blood flow. Male Wistar rats were divided into 4 series (A-D) of the experimental groups (n=7). In series A the importance of peripherally administered ghrelin at different time of I/R period was studied. In series B the importance of centrally administered ghrelin at different time of I/R period was evaluated. In series C and D, the mechanisms of peripherally and centrally administered hormone were examined, respectively. Two models of the I/R period were selected: short lasting (30/60 min) and long lasting (60/120 min). The following drugs were used: ghrelin (50 µg/kg i.p. or 1 nmol in 10 µl i.c.v.), 6 hydroxy dopamine (50 mg/kg i.p.), nadolol (0.5 mg/kg i.p.), calcitonin gene related peptide fragment (CGRP(8-37), 100 µg /kg i.p.), capsaicin (5-10 mg/100 ml solution s.c.). The mesenteric blood flow (MBF-ml/min), the intestinal microcirculatory blood flow (LDBF-PU), the arterio-venous oxygen difference (AVO(2)-ml/O(2)/100 ml blood), and the intestinal oxygen uptake (VO(2)) in ml O(2)/min were measured. Mucosal impairment was assessed planimetrically with the use of a digital photo analyzer (LA) and histologically with the use of the six-point Park/Chiu scale. Peripheral administration of ghrelin evoked marked increase of MBF and LDBF by 42% and 48%, respectively, with significant reduction of LA by 38%. When ghrelin was administered at the beginning of the reperfusion period during the short I/R period or prior to the long lasting I/R period, the vascular reactions and protective effects were reduced, but not completely abolished. The central administration of ghrelin before the short I/R period significantly increased the MBF and LDBF by about 32% and 35%, respectively, as well as LA reduction by about 20% in comparison to the control group. However, when ghrelin was administered prior to the long I/R period or after the onset of completed ischemia, neither vascular nor protective effects were noticed. Sensory denervation and the blockade of the CGRP1 receptors totally blocked the protective and hyperemic effects of the peripherally administered ghrelin. Selective blockade of the adrenergic system or blunting of the vagal nerves (vagotomy) significantly but not totally eliminated the effects of centrally applied ghrelin, which were abolished when both adrenergic and parasympathetic pathways were ablated. These results indicate that ghrelin applied centrally or peripherally markedly increases resistance of the intestinal tissue during the I/R period induced mucosal and hyperemic impairment evoked by I/R. Ghrelin is an important mediator of the increase in the intestinal microcirculation and elevation of the intestinal metabolism, which seems to be, at least in part, responsible for the observed protection of the intestine subjected to I/R. Impairment of this microvasculature response due to I/R seems to be responsible for a markedly observed weaker effect of ghrelin when this hormone was administered after the ischemic period. The lack of a protective effect observed after central administration of this peptide against a long lasting I/R period is probably due to damage of neural pathways caused by I/R. Finally, the peripheral activity of ghrelin in the intestine is mediated by the sensory neurons with a prominent role of CGRP released from their endings. However, this peripheral action of ghrelin depends upon the proper functioning of both the sympathetic and parasympathetic system.
Asunto(s)
Ghrelina/administración & dosificación , Ghrelina/uso terapéutico , Mucosa Intestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Oclusión Vascular Mesentérica/prevención & control , Daño por Reperfusión/prevención & control , Vías Aferentes/efectos de los fármacos , Animales , Capsaicina/farmacología , Modelos Animales de Enfermedad , Esquema de Medicación , Ghrelina/metabolismo , Ghrelina/farmacología , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/inervación , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Intestino Delgado/irrigación sanguínea , Intestino Delgado/inervación , Intestino Delgado/metabolismo , Intestino Delgado/patología , Masculino , Oclusión Vascular Mesentérica/etiología , Oclusión Vascular Mesentérica/metabolismo , Oclusión Vascular Mesentérica/patología , Microcirculación/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Ghrelina/metabolismo , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Circulación Esplácnica/efectos de los fármacos , Simpatectomía Química , Factores de Tiempo , VagotomíaRESUMEN
OBJECTIVE: A disintegrin and metalloprotease with thrombospondin type 1 repeats-13 (ADAMTS13) inhibits platelet aggregation and arterial thrombosis by cleavage of von Willebrand factor. However, the structural components of ADAMTS13 required for inhibition of arterial thrombosis are not fully defined. METHODS AND RESULTS: Using recombinant proteins and a murine model, we demonstrated that an ADAMTS13 variant truncated after either the eighth thrombospondin type 1 repeat or the spacer domain inhibits ferric chloride-induced arterial thrombosis in ADAMTS13(-/-) mice with efficacy similar to that of full-length ADAMTS13. The results obtained from monitoring thrombus formation in carotid and mesenteric arteries were highly concordant. Further analyses by site-directed mutagenesis and human monoclonal antibody inhibition assay revealed that the Cys-rich and spacer domains of ADAMTS13, particularly the amino acid residues between Arg559 and Glu664 in the spacer domain, may be critical for modulation of arterial thrombosis in vivo. Finally, the thrombosis-modulating function of ADAMTS13 and variants/mutants was highly correlated with the von Willebrand factor-cleavage activity under fluid shear stress. CONCLUSIONS: Our results suggest that the amino terminus of ADAMTS13, specifically the variable region of the spacer domain, is crucial for modulation of arterial thromboses under (patho)physiological conditions. These findings shed more light on the structure-function relationship of ADAMTS13 in vivo and may be applicable for rational design of protein- or gene-based therapy of arterial thromboses.
Asunto(s)
Proteínas ADAM/metabolismo , Estenosis Carotídea/prevención & control , Oclusión Vascular Mesentérica/prevención & control , Metaloendopeptidasas/metabolismo , Trombosis/prevención & control , Proteínas ADAM/sangre , Proteínas ADAM/química , Proteínas ADAM/genética , Proteínas ADAM/inmunología , Proteína ADAMTS13 , Animales , Anticuerpos Monoclonales , Estenosis Carotídea/sangre , Estenosis Carotídea/inducido químicamente , Estenosis Carotídea/enzimología , Estenosis Carotídea/genética , Cloruros , Modelos Animales de Enfermedad , Perros , Compuestos Férricos , Células HEK293 , Semivida , Humanos , Cinética , Oclusión Vascular Mesentérica/inducido químicamente , Oclusión Vascular Mesentérica/enzimología , Oclusión Vascular Mesentérica/genética , Metaloendopeptidasas/química , Metaloendopeptidasas/deficiencia , Metaloendopeptidasas/genética , Ratones , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Mutación , Estructura Terciaria de Proteína , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Trombosis/sangre , Trombosis/inducido químicamente , Trombosis/enzimología , Trombosis/genética , Transfección , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: We previously described a model of laser-induced thrombosis in mesenteric arterioles with superficial and deep levels of injury producing a transient thrombus resolving within 2 min and a larger almost occlusive thrombus, respectively. Both types of lesion were sensitive to platelet GPIIb-IIIa and P2Y(12) inhibition, whereas only deep injuries were sensitive to thrombin blockade. OBJECTIVE: The aim of the present study was to use histologic methods and electron and intravital microscopy to characterize the lesions and thrombi and to extend our knowledge of the sensitivity of this model to genetic and pharmacologic inhibition. RESULTS: A superficial injury was found to detach the endothelial cells and expose a collagen III- and IV-rich subendothelium where platelets could adhere. Tissue factor and fibrin were not detected. Deeper penetration of the external elastic lamina occurred in deep injuries, with exposure of collagen I, III and IV. Here the thrombus was composed of platelets exhibiting a decreasing gradient of degranulation from the deepest lesion area to the surface. Fibrin was found close to the most activated platelets. Consistently, glycoprotein VI (GPVI)-collagen and GPIb-von Willebrand factor (VWF) interactions were found to be critical in superficial injuries. After deep lesion, thrombus formation was modestly reduced in GPVI-immunodepleted mice and still strongly inhibited in VWF(-/-) mice. Combined hirudin infusion and GPVI depletion further inhibited thrombosis after deep injury. CONCLUSIONS: This study confirms the feasibility of inducing arterial thrombosis with distinct levels of severity and establishes the central roles of collagen and VWF in thrombus formation after superficial injury. Collagen, VWF and thrombin all appear to contribute to thrombosis after deep arterial lesion.
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Plaquetas/ultraestructura , Endotelio Vascular/ultraestructura , Arterias Mesentéricas/ultraestructura , Oclusión Vascular Mesentérica/patología , Adhesividad Plaquetaria , Trombosis/patología , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Colágeno Tipo IV/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/lesiones , Endotelio Vascular/metabolismo , Estudios de Factibilidad , Fibrina/metabolismo , Fibrinolíticos/administración & dosificación , Hirudinas/administración & dosificación , Inyecciones Subcutáneas , Láseres de Gas , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/lesiones , Arterias Mesentéricas/metabolismo , Oclusión Vascular Mesentérica/sangre , Oclusión Vascular Mesentérica/etiología , Oclusión Vascular Mesentérica/prevención & control , Ratones , Ratones Noqueados , Adhesividad Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/deficiencia , Glicoproteínas de Membrana Plaquetaria/metabolismo , Índice de Severidad de la Enfermedad , Trombosis/sangre , Trombosis/etiología , Trombosis/prevención & control , Factores de Tiempo , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismoRESUMEN
3,4-dihydroxy-phenyl lactic acid (DLA) and salvianolic acid B (SAB) are two major water-soluble components of Salvia miltiorrhiza (SM). Previous works have revealed the ability of DLA and SAB to scavenge oxygen free radicals, inhibiting the expression of adhesion molecules CD11b/CD18 in neutrophil. Cardiotonic pills (CP), which is a traditional Chinese medicine compound preparation containing DLA and SAB, was found to inhibit venular thrombosis induced by photochemical reaction (PR) in rat mesentery. The present study addressed the effect of DLA and SAB on PR-induced thrombosis in rat mesentery by utilizing a microcirculation dynamic viewing system. The result demonstrated that both DLA and SAB delayed thrombus-initiation time, while DLA also prolonged thrombus half-size time. The experiments explored the mechanism underlying that the dihydrorhodamine 123 (DHR) fluorescence in the mesenteric venular walls after PR challenge was diminished by pretreatment with either DLA or SAB, the expression of CD18 in neutrophils elicited by PR was depressed by administration of DLA, while mast cell degranulation in rat mesentery induced by PR was damped by SAB. The antioxidant potential of the two substances is likely to be responsible for their most beneficial effects on thrombosis, through either directly scavenging the peroxides produced and/or indirectly depressing the expression of adhesion molecules in neutrophil.
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Antioxidantes/farmacología , Benzofuranos/farmacología , Medicamentos Herbarios Chinos/farmacología , Lactatos/farmacología , Trombosis de la Vena/prevención & control , Animales , Antígenos CD18/efectos de los fármacos , Antígenos CD18/metabolismo , Canfanos , Fotorradiación con Hematoporfirina/efectos adversos , Masculino , Mastocitos/efectos de los fármacos , Oclusión Vascular Mesentérica/prevención & control , Venas Mesentéricas , Neutrófilos/efectos de los fármacos , Panax notoginseng , Ratas , Salvia miltiorrhizaRESUMEN
Portal vein thrombosis after laparoscopy became an issue of interest with the technological progress in surgery (the expanding use of minimally invasive approach) and imaging (the higher availability of Doppler ultrasonography and spiral computer tomography). Along with the extensive interest for laparoscopy in our country, a guideline for the prophylaxis and treatment of this potentially deadly complication seems necessary. Portal vein thrombosis (PVT) should be promptly diagnosed and treated to prevent its extension to the superior mesenteric venous system, as it may sometime trigger a potentially life-threatening complication, the entero-mesenteric venous infarction. It is acknowledged that the increasing use of laparoscopy in the last decades represents a major therapeutical progress. The effects of this approach are still to be explored.
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Laparoscopía/efectos adversos , Vena Porta , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiología , Anticoagulantes/uso terapéutico , Humanos , Incidencia , Oclusión Vascular Mesentérica/prevención & control , Factores de Riesgo , Rumanía/epidemiología , Esplenectomía/efectos adversos , Resultado del Tratamiento , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/tratamiento farmacológicoRESUMEN
PURPOSE: To evaluate the effect of the ischemic preconditioning and the ischemic postconditioning over the tissue injury in the intestinal mucosa of rats undergoing the procedure of mesenteric ischemia and reperfusion. METHODS: Thirty Wistar rats were studied, divided in three groups: group A, undergoing mesenteric ischemia (30 minutes) and reperfusion (60 minutes); group B, mesenteric ischemia and reperfusion preceded by ischemic preconditioning; group C, mesenteric ischemia and reperfusion and, before the beginning of reperfusion, the ischemic postconditioning was performed. At the end, a segment of the small intestine was dissected for histological analysis. The results were evaluated using the CHIU et al.6 classification followed by the statistic treatment. RESULTS: The mean values of the tissue injury levels were: group A, 3.5; group B, 1.2; and group C, 1. The difference between the result of group A with the results of groups B and C was considered statistically significant (p < 0,05). CONCLUSION: The ischemic preconditioning and postconditioning are able to minimize the tissue injury in the intestines of rats that underwent the procedure of mesenteric ischemia and reperfusion.
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Mucosa Intestinal/irrigación sanguínea , Intestino Delgado/irrigación sanguínea , Precondicionamiento Isquémico/métodos , Oclusión Vascular Mesentérica/prevención & control , Daño por Reperfusión/prevención & control , Animales , Modelos Animales de Enfermedad , Mucosa Intestinal/patología , Intestino Delgado/patología , Masculino , Arteria Mesentérica Superior , Oclusión Vascular Mesentérica/patología , Ratas , Ratas Wistar , Daño por Reperfusión/patología , Estadísticas no ParamétricasRESUMEN
PURPOSE: To evaluate the effect of the ischemic preconditioning and the ischemic postconditioning over the tissue injury in the intestinal mucosa of rats undergoing the procedure of mesenteric ischemia and reperfusion. METHODS: Thirty Wistar rats were studied, divided in three groups: group A, undergoing mesenteric ischemia (30 minutes) and reperfusion (60 minutes); group B, mesenteric ischemia and reperfusion preceded by ischemic preconditioning; group C, mesenteric ischemia and reperfusion and, before the beginning of reperfusion, the ischemic postconditioning was performed. At the end, a segment of the small intestine was dissected for histological analysis. The results were evaluated using the CHIU et al.6 classification followed by the statistic treatment. RESULTS: The mean values of the tissue injury levels were: group A, 3.5; group B, 1.2; and group C, 1. The difference between the result of group A with the results of groups B and C was considered statistically significant (p < 0,05). CONCLUSION: The ischemic preconditioning and postconditioning are able to minimize the tissue injury in the intestines of rats that underwent the procedure of mesenteric ischemia and reperfusion.
OBJETIVO: Avaliar o efeito do pré e pós-condicionamento isquêmico sobre a lesão tecidual na mucosa intestinal de ratos submetidos ao processo de isquemia e reperfusão mesentérica. MÉTODOS: Foram estudados 30 ratos Wistar, distribuídos em três grupos: grupo A, em que se realizou isquemia (30 minutos) e reperfusão (60 minutos) mesentérica; grupo B, isquemia e reperfusão mesentérica precedidos pelo pré-condicionamento isquêmico; grupo C, isquemia e reperfusão mesentérica e, precedendo o início da reperfusão, foi realizado o pós-condicionamento isquêmico. Ao final, ressecou-se um segmento do intestino delgado para análise histológica. Avaliaram-se os resultados pela classificação de CHIU e col.6 e procedeu-se o tratamento estatístico. RESULTADOS: As médias dos graus de lesão tecidual foram: grupo A, 3,5; grupo B, 1,2; grupo C, 1. A diferença entre o resultado do grupo A com os resultados dos grupos B e C foi considerada estatisticamente significativa (p < 0,05). CONCLUSÃO: O pré e pós-condicionamento isquêmico foram capazes de minimizar a lesão tecidual na mucosa intestinal de ratos submetidos ao processo de isquemia e reperfusão mesentérica.
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Animales , Masculino , Ratas , Mucosa Intestinal/irrigación sanguínea , Intestino Delgado/irrigación sanguínea , Precondicionamiento Isquémico/métodos , Oclusión Vascular Mesentérica/prevención & control , Daño por Reperfusión/prevención & control , Modelos Animales de Enfermedad , Mucosa Intestinal/patología , Intestino Delgado/patología , Arteria Mesentérica Superior , Oclusión Vascular Mesentérica/patología , Ratas Wistar , Daño por Reperfusión/patología , Estadísticas no ParamétricasAsunto(s)
Aneurisma de la Aorta Abdominal/cirugía , Colitis Isquémica/etiología , Colon Sigmoide/irrigación sanguínea , Arteria Mesentérica Inferior/cirugía , Reimplantación/métodos , Procedimientos Quirúrgicos Vasculares/efectos adversos , Procedimientos Quirúrgicos Vasculares/métodos , Colitis Isquémica/prevención & control , Humanos , Oclusión Vascular Mesentérica/complicaciones , Oclusión Vascular Mesentérica/prevención & control , Complicaciones Posoperatorias , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Replanting the inferior mesentery artery (IMA) to prevent ischemic colitis (IC) has been discussed for many years; yet, to our knowledge, no prospective studies have been conducted to compare the incidence of histologically proven IC in patients with and without IMA revascularization. The aim of this prospective study, with histologic evaluation of the sigmoid colon mucosa, was to assess the influence of replanting the IMA on IC and mortality. METHODS: From January 1999 to December 2003, 160 consecutive patients who were operated on for a symptomatic (n = 21) or asymptomatic (n = 139) infrarenal aortic aneurysm were prospectively assessed and randomly assigned either to replanting or ligating the IMA. Sigmoidoscopy with biopsy was performed on day 4 or 5 after surgery; an autopsy was performed on patients not surviving to day 5 after surgery. All patients gave written informed consent. RESULTS: Of the 160 randomized patients, 128 had a confirmed patent IMA and formed the basis of this study. Their age was 70 +/- 8 years (men, 70 +/- 8 years; women, 73 +/- 7 years). The IMA was replanted in 67 patients (52%) and ligated in 61 (48%) intraoperatively. IC developed in six patients with a replanted IMA and in 10 with a ligated IMA (relative risk [RR], 0.55; 95% confidence interval [CI], 0.21 to 1.41; chi2 = 1.62; P = .203). Blood loss in the two cohorts did not differ significantly (P = .788); however, patients with IC had a significantly higher blood loss compared with the cohort without IC (P = .012) and were older (P = .017). Age, sex distribution, clamping time, the use of tube or bifurcated grafts, and intraoperative hypotension did not differ between patients with ligated or replanted IMA. CONCLUSION: Although replanting the IMA did not confer a statistically significant reduction of perioperative morbidity or mortality in this study, it appears that older patients and patients with increased intraoperative blood loss might benefit from IMA replantation, because this maneuver does not increase perioperative morbidity or substantially increase operation time.
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Aneurisma de la Aorta Abdominal/cirugía , Implantación de Prótesis Vascular/métodos , Colitis Isquémica/prevención & control , Colon Sigmoide/patología , Arteria Mesentérica Inferior/cirugía , Reimplantación/métodos , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/mortalidad , Implantación de Prótesis Vascular/mortalidad , Colitis Isquémica/patología , Intervalos de Confianza , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/patología , Masculino , Oclusión Vascular Mesentérica/prevención & control , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Probabilidad , Estudios Prospectivos , Radiografía , Valores de Referencia , Arteria Renal/cirugía , Medición de Riesgo , Sigmoidoscopía/métodos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Acute mesenteric ischemia (AMI) is a serious condition with high mortality rate due to difficult and late diagnosis. Early and aggressive evaluation in high risk patients by mesenteric angiography is the key to the reduction in mortality rate. However; many physicians hesitated to perform it because of its availability, the risk of complications and high negative results. This study reviewed outcome of AMI in term of mortality rate, factors associated with mortality and the rate of angiography in high risk patients. MATERIAL AND METHOD: The clinical data of the patients who were diagnosed as AMI were retrospectively reviewed. The clinical outcome was recorded and the factors associated with mortality were analysed. RESULTS: Thirty-five patients were enrolled into this study during 5 years. The mortality rate was 74.3%. There were 22 high risk patients for AMI. The rate of angiography performed in this group was 4.5% (1/22). The factors associated with mortality were age more than 60 years, patients with peritonitis, hypotension, arterial cause, time interval between admission and operation or treatment more than 24 hours, bowel gangrene >100 cms. However all these factors were not statistically significant. CONCLUSION: The mortality rate of AMI is still high even at the tertiary hospital where the angiography is available 24 hours. To decrease the mortality rate, the physicians must have the high index of suspicion in high risk patients and do not hesitate to perform early mesenteric angiography.
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Isquemia/mortalidad , Arterias Mesentéricas/diagnóstico por imagen , Oclusión Vascular Mesentérica/mortalidad , Resultado del Tratamiento , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Angiografía , Femenino , Humanos , Isquemia/diagnóstico por imagen , Isquemia/prevención & control , Masculino , Oclusión Vascular Mesentérica/diagnóstico por imagen , Oclusión Vascular Mesentérica/prevención & control , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
Kinetin has been shown to have anti-aging effects on several different systems, including plants and human cells. Recently, we demonstrated that kinetin markedly inhibited platelet aggregation in washed human platelets. In the present study, an electron spin resonance (ESR) method was used to further evaluate the scavenging activity of kinetin on the free radicals formed. Kinetin (70 and 150 microM) concentration dependently reduced the ESR signal intensity of hydroxyl radicals in collagen (1 microg/ml)-activated platelets. Furthermore, kinetin was effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism in mice when administered intravenously at doses of 4 and 6 mg/kg. In addition, intravenous injection of kinetin (4 and 6 mg/kg) significantly prolonged the bleeding time by approximately 1.9- and 2.1-fold as compared with normal saline in severed mesenteric arteries of rats. A continuous infusion of kinetin (0.6 mg/kg/min) for 10 min also significantly increased the bleeding time by about 2.3-fold, and the bleeding time returned to baseline within 120 min after cessation of kinetin infusion. Platelet thrombi formation was induced by irradiation of mesenteric venules with filtered light in mice pretreated intravenously with fluorescein sodium. When kinetin was administered at 13 and 14 mg/kg in mice pretreated with fluorescein sodium (5 mg/kg), the occlusion time was significantly prolonged. In conclusion, these results suggest that kinetin has effective free radical-scavenging activity in vitro and antithrombotic activity in vivo. Treatment with kinetin may lower the risk of thromboembolic-related disorders. Therefore, kinetin may be a potential therapeutic agent for arterial thrombosis, but its toxicity must be further assessed.